Sildenafil in the treatment of pulmonary hypertension

The therapy of pulmonary hypertension has evolved rapidly in the last 10 years from the use of non-selective vasodilators to drugs that specifically target pulmonary vasodilation, endothelial function, and vascular remodeling. Sildenafil is a phosphodiesterase type 5 inhibitor that has an expanding role in the treatment of pulmonary hypertension. Case series and small studies, as well as the first large randomized controlled trial, have demonstrated the safety and efficacy of sildenafil in improving mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and exercise tolerance in pulmonary arterial hypertension. It may be useful in adults, children, and neonates after cardiac surgery, with left heart failure, in fibrotic pulmonary disease, high altitude exposure, and thromboembolic disease, and in combination with other therapies for pulmonary hypertension, such as inhaled iloprost. The oral formulation and favorable adverse effect profile make sildenafil an attractive alternative in the treatment of selected patients with pulmonary hypertension

Vascular complications of sickle cell disease

Sickle cell disease (SCD) is a monogenetic disorder caused by a mutation in the [H9252]-globin gene HBB leading to polymerization of red blood cells causing damage to cell membranes, increasing its rigidity and intravascular hemolysis. Multiple lines of evidence suggest that SCD can be viewed as pan-vasculopathy associated with multiple mechanisms but driven by hemoglobin S polymerization. Here we review the pathophysiology, clinical manifestations and management strategies for cerebrovascular disease, pulmonary hypertension and renal disease associated with SCD. These “vascular phenotypes” reflect the systemic nature of the complications of SCD and are a major threat to the well-being of patients with the disorder

Micro-RNA-1 is decreased by hypoxia and contributes to the development of pulmonary vascular remodeling via regulation of sphingosine kinase 1

Sphingosine kinase 1 (SphK1) upregulation is associated with pathologic pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), but the mechanisms controlling its expression are undefined. In this study, we sought to characterize the regulation of SphK1 expression by micro-RNAs (miRs). In silico analysis of the SphK1 3'-untranslated region identified several putative miR binding sites, with miR-1-3p (miR-1) being the most highly predicted target. Therefore we further investigated the role of miR-1 in modulating SphK1 expression and characterized its effects on the phenotype of pulmonary artery smooth muscle cells (PASMCs) and the development of experimental pulmonary hypertension in vivo. Our results demonstrate that miR-1 is downregulated by hypoxia in PASMCs and can directly inhibit SphK1 expression. Overexpression of miR-1 in human PASMCs inhibits basal and hypoxia-induced proliferation and migration. Human PASMCs isolated from PAH patients exhibit reduced miR-1 expression. We also demonstrate that miR-1 is downregulated in mouse lung tissues during experimental hypoxia-mediated pulmonary hypertension (HPH), consistent with upregulation of SphK1. Furthermore, administration of miR-1 mimics in vivo prevented the development of HPH in mice and attenuated induction of SphK1 in PASMCs. These data reveal the importance of miR-1 in regulating SphK1 expression during hypoxia in PASMCs. A pivotal role is played by miR-1 in pulmonary vascular remodeling, including PASMC proliferation and migration, and its overexpression protects from the development of HPH in vivo. These studies improve our understanding of the molecular mechanisms underlying the pathogenesis of pulmonary hypertension

MicroRNA410 Inhibits Pulmonary Vascular Remodeling via Regulation of Nicotinamide Phosphoribosyltransferase

Nicotinamide phosphoribosyltransferase (NAMPT) upregulation in human pulmonary artery endothelial cells (hPAECs) is associated with pulmonary arterial hypertension (PAH) progression and pulmonary vascular remodeling. The underlying mechanisms regulating NAMPT expression are still not clear. In this study, we aimed to study the regulation of NAMPT expression by microRNA410 (miR410) in hPAECs and explore the role of miR410 in the pathogenesis of experimental pulmonary hypertension. We show that miR410 targets the 3' UTR of NAMPT and that, concomitant with NAMPT upregulation, miR410 is downregulated in lungs of mice exposed to hypoxia-induced pulmonary hypertension (HPH). Our results also demonstrate that miR410 directly inhibits NAMPT expression. Overexpression of miR410 in hPAECs inhibits basal and VEGF-induced proliferation, migration and promotes apoptosis of hPAECs, while miR410 inhibition via antagomirs has the opposite effect. Finally, administration of miR410 mimics in vivo attenuated induction of NAMPT in PAECs and prevented the development of HPH in mice. Our results highlight the role of miR410 in the regulation of NAMPT expression in hPAECs and show that miR410 plays a potential role in PAH pathobiology by targeting a modulator of pulmonary vascular remodeling

Vesicle formation induced by thermal fluctuations

The process of fission and vesicle formation depends on the geometry of the membrane that will split. For instance, a flat surface finds it difficult to form vesicles because of the lack of curved regions where to start the process. Here we show that vesicle formation can be promoted by temperature, by using a membrane phase field model with Gaussian curvature. We find a phase transition between fluctuating and vesiculation phases that depends on temperature, spontaneous curvature, and the ratio between bending and Gaussian moduli. We analysed the energy dynamical behaviour of these processes and found that the main driving ingredient is the Gaussian energy term, although the curvature energy term usually helps with the process as well. We also found that the chemical potential can be used to investigate the temperature of the system. Finally we address how temperature changes the condition for spontaneous vesiculation for all geometries, making it happen in a wider range of values of the Gaussian modulus.Comment: 31 pages, 10 figure

Análise morfométrica e de usos do solo da bacia hidrográfica do Arroio Candiota, RS, Brasil

The Knowledge of the natural and anthropogenic factors at watershed scale is crucial to management of water resources, considering that the river systems are organized hierarchically. In this sense, this study aims to describe the morphometric characteristics of relief and drainage network as well as land use in the Arroio Candiota watershed, RS, Brazil. For this, 26 catchments were selected to analyze 15 morphometric variables and eight land use classes. In general, the catchments showed low drainage density and streams with low sinuosity. Circularity ratio, relief ratio, slope and topographic factor were inversely correlated with the catchment area. Therefore, the smaller catchments tend to have greater potential for erosion in their main channel and increased susceptibility to flooding, because it is more likely the entire catchment be achieved simultaneously by rainfall. Most of the Arroio Candiota watershed (59.31 %), mainly its eastern portion, is occupied by natural vegetation. Mining and forestry are associated with the regions nearby of headwaters of streams while agriculture and degraded prairies are distributed closer to the main course of the Arroio Candiota. This study demonstrates that the morphometric characteristics and land use vary spatially in Arroio Candiota watershed and the distribution of some human activities is related to natural features such as relief and water availability.O conhecimento dos fatores naturais e antrópicos que operam em escala de bacia hidrográfica é crucial para a gestão dos recursos hídricos, tendo em vista que os sistemas fluviais se organizam de forma hierárquica. Nesse sentido, este estudo tem por objetivo descrever as características morfométricas do relevo e da rede de drenagem, assim como, os usos do solo presentes na bacia hidrográfica do Arroio Candiota, RS, Brasil. Para isso, foram selecionadas 26 sub-bacias para análise de 15 variáveis morfométricas e oito classes de usos do solo. As sub-bacias em geral possuem riachos pouco sinuosos e baixa densidade de drenagem. Razão de circularidade, relação de relevo, declive e fator topográfico mostraram-se inversamente correlacionadas com a área das sub-bacias. Logo, as sub-bacias menores tendem a apresentar, no seu rio principal, um maior potencial de erosão e ser mais suscetíveis à inundação, pois é maior a probabilidade da sub-bacia inteira ser atingida simultaneamente pela chuva. A maior parte da bacia hidrográfica do Arroio Candiota (59,31 %), principalmente a sua metade leste, é ocupada por vegetação natural. As atividades de mineração e silvicultura estão mais associadas às regiões próximas às nascentes dos riachos enquanto agricultura e campo degradado se distribuem mais próximas ao curso principal do Arroio Candiota. Este estudo demonstra que as características morfométricas e os usos do solo variam espacialmente na bacia hidrográfica do Arroio Candiota e a distribuição de algumas atividades antrópicas está relacionada a características naturais, como relevo e disponibilidade hídrica

Updated Clinical Classification of Pulmonary Hypertension

In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1. Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4

Chromosomal painting and ZW sex chromosomes differentiation in Characidium (Characiformes, Crenuchidae)

<p>Abstract</p> <p>Background</p> <p>The <it>Characidium </it>(a Neotropical fish group) have a conserved diploid number (2n = 50), but show remarkable differences among species and populations in relation to sex chromosome systems and location of nucleolus organizer regions (NOR). In this study, we isolated a W-specific probe for the <it>Characidium </it>and characterized six <it>Characidium </it>species/populations using cytogenetic procedures. We analyzed the origin and differentiation of sex and NOR-bearing chromosomes by chromosome painting in populations of <it>Characidium </it>to reveal their evolution, phylogeny, and biogeography.</p> <p>Results</p> <p>A W-specific probe for efficient chromosome painting was isolated by microdissection and degenerate oligonucleotide primed-polymerase chain reaction (DOP-PCR) amplification of W chromosomes from <it>C. gomesi</it>. The W probe generated weak signals dispersed on the proto sex chromosomes in <it>C. zebra</it>, dispersed signals in both W and Z chromosomes in <it>C. lauroi </it>and, in <it>C. gomesi </it>populations revealed a proximal site on the long arms of the Z chromosome and the entire W chromosome. All populations showed small terminal W probe sites in some autosomes. The 18S rDNA revealed distinctive patterns for each analyzed species/population with regard to proto sex chromosome, sex chromosome pair, and autosome location.</p> <p>Conclusions</p> <p>The results from dual-color fluorescence <it>in situ </it>hybridization (dual-color FISH) using W and 18S rDNA probes allowed us to infer the putative evolutionary pathways for the differentiation of sex chromosomes and NORs, from structural rearrangements in a sex proto-chromosome, followed by gene erosion and heterochromatin amplification, morphological differentiation of the sex chromosomal pair, and NOR transposition, giving rise to the distinctive patterns observed among species/populations of <it>Characidium</it>. Biogeographic isolation and differentiation of sex chromosomes seem to have played a major role in the speciation process in this group of fish.</p

Peripheral Blood Gene Expression as a Novel Genomic Biomarker in Complicated Sarcoidosis

Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ∼20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis.</p